The present invention relates to spiropiperidine derivatives, their synthesis, and their use as melanocortin receptor (MC-R) agonists. More particularly, the compounds of the present invention are selective agonists of the melanocortin-4 receptor (MC-4R) and are thereby useful for the treatment of disorders responsive to the activation of MC-4R, such as obesity, diabetes, and male and/or female sexual dysfunction.
Pro-opiomelanocortin (POMC) derived peptides are known to affect food intake. Several lines of evidence support the notion that the G-protein coupled receptors (GPCRs) of the melanocortin receptor (MC-R) family, several of which are expressed in the brain, are the targets of POMC derived peptides involved in the control of food intake and metabolism. A specific single MC-R that may be targeted for the control of obesity has not yet been identified, although evidence has been presented that MC-4R signalling is important in mediating feed behavior (S.Q. Giraudo et al., xe2x80x9cFeeding effects of hypothalamic injection of melanocortin-4 receptor ligands,xe2x80x9d Brain Research, 80: 302-306 (1998)).
Evidence for the involvement of MC-R""s in obesity includes: i) the agouti (Avy) mouse which ectopically expresses an antagonist of the MC-1R, MC-3R and -4R is obese, indicating that blocking the action of these three MC-R""s can lead to hyperphagia and metabolic disorders; ii) MC-4R knockout mice (D. Huszar et al., Cell, 88: 131-141 (1997)) recapitulate the phenotype of the agouti mouse and these mice are obese; iii) the cyclic heptapeptide MT-II (a non-selective MC-1R, -3R, 4R, and -5R agonist) injected intracerebroventricularly (ICV) in rodents, reduces food intake in several animal feeding models (NPY, ob/ob, agouti, fasted) while ICV injected SHU-9119 (MC-3R and 4R antagonist; MC-1R and -5R agonist) reverses this effect and can induce hyperphagia; iv) chronic intraperitoneal treatment of Zucker fatty rats with an xcex1-NDP-MSH derivative (HP228) has been reported to activate MC-1R, -3R, -4R, and -5R and to attenuate food intake and body weight gain over a 12-week period (I. Corcos et al., xe2x80x9cHP228 is a potent agonist of melanocortin receptor-4 and significantly attenuates obesity and diabetes in Zucker fatty rats,xe2x80x9d Society for Neuroscience abstracts, 23: 673 (1997)).
Five distinct MC-R""s have thus far been identified, and these are expressed in different tissues. MC-1R was initially characterized by dominant gain of function mutations at the Extension locus, affecting coat color by controlling phaeomelanin to eumelanin conversion through control of tyrosinase. MC-1R is mainly expressed in melanocytes. MC-2R is expressed in the adrenal gland and represents the ACTH receptor. MC-3R is expressed in the brain, gut, and placenta and may be involved in the control of food intake and thermogenesis. MC-4R is uniquely expressed in the brain, and its inactivation was shown to cause obesity (A. Kask, et al., xe2x80x9cSelective antagonist for the melanocortin-4 receptor (HS014) increases food intake in free-feeding rats,xe2x80x9d Biochem. Biophys. Res. Commun., 245: 90-93 (1998)). MC-5R is expressed in many tissues, including white fat, placenta and exocrine glands. A low level of expression is also observed in the brain. MC-5R knockout mice reveal reduced sebaceous gland lipid production (Chen et al., Cell, 91: 789-798 (1997)).
Erectile dysfunction denotes the medical condition of inability to achieve penile erection sufficient for successful sexual intercourse. The term xe2x80x9cimpotencexe2x80x9d is oftentimes employed to describe this prevalent condition. Approximately 140 million men worldwide, and, according to a National Institutes of Health study, about 30 million American men suffer from impotency or erectile dysfunction. It has been estimated that the latter number could rise to 47 million men by the year 2000. Erectile dysfunction can arise from either organic or psychogenic causes, with about 20% of such cases being purely psychogenic in origin. Erectile dysfunction increases from 40% at age 40, to 67% at age 75, with over 75% occurring in men over the age of 50. In spite of the frequent occurrence of this condition, only a small number of patients have received treatment because existing treatment alternatives, such as injection therapies, penile prosthesis implantation, and vacuum pumps, have been uniformly disagreeable [for a discussion, see xe2x80x9cABC of sexual healthxe2x80x94erectile dysfunction,xe2x80x9d Brit. Med. J. 318: 387-390 (1999)]. Only more recently have more viable treatment modalities become available, in particular orally active agents, such as sildenafil citrate, marketed by Pfizer under the brand name of Viagra(copyright). Sildenafil is a selective inhibitor of type V phosphodiesterase (PDE-V), a cyclic-GMP-specific phosphodiesterase isozyme [see R. B. Moreland et al., xe2x80x9cSildenafil: A Novel Inhibitor of Phosphodiesterase Type 5 in Human Corpus Cavernosum Smooth Muscle Cells,xe2x80x9d Life Sci., 62: 309-318 (1998)]. Prior to the introduction of Viagra on the market, less than 10% of patients suffering from erectile dysfunction received treatment. Sildenafil is also being evaluated in the clinic for the treatment of female sexual dysfunction.
The regulatory approval of Viagra(copyright) for the oral treatment of erectile dysfunction has invigorated efforts to discover even more effective methods to treat erectile dysfunction. Several additional selective PDE-V inhibitors are in clinical trials. UK-114542 is a sildenafil backup from Pfizer with supposedly improved properties. IC-351 (ICOS Corp.) is claimed to have greater selectivity for PDE-V over PDE-VI than sildenafil. Other PDE-V inhibitors include M-54033 and M-54018 from Mochida Pharmaceutical Co. and E-4010 from Eisai Co., Ltd.
Other pharmacological approaches to the treatment of erectile dysfunction have been described [see, e.g., xe2x80x9cLatest Findings on the Diagnosis and Treatment of Erectile Dysfunction,xe2x80x9d Drug News and Perspectives, 9: 572-575 (1996); xe2x80x9cOral Pharmacotherapy in Erectile Dysfunction,xe2x80x9d Current Opinion in Urology, 7: 349-353 (1997)]. A product under clinical development by Zonagen is an oral formulation of the alpha-adrenoceptor antagonist phentolamine mesylate under the brand name of Vasomax(copyright). Vasomax(copyright) is also being evaluated for the treatment of female sexual dysfunction.
Drugs to treat erectile dysfunction act either peripherally or centrally. They are also classified according to whether they xe2x80x9cinitiatexe2x80x9d a sexual response or xe2x80x9cfacilitatexe2x80x9d a sexual response to prior stimulation [for a discussion, see xe2x80x9cA Therapeutic Taxonomy of Treatments for Erectile Dysfunction: An Evolutionary Imperative,xe2x80x9d Int. J. Impotence Res., 9: 115-121 (1997)]. While sildenafil and phentolamine act peripherally and are considered to be xe2x80x9cenhancersxe2x80x9d or xe2x80x9cfacilitatorsxe2x80x9d of the sexual response to erotic stimulation, sildenafil appears to be efficacious in both mild organic and psychogenic erectile dysfunction. Sildenafil has an onset of action of 30-60 minutes after an oral dose with the effect lasting about 4 hours, whereas phentolamine requires 5-30 minutes for onset with a duration of 2 hours. Although sildenafil is effective in a majority of patients, it takes a relatively long time for the compound to show the desired effects. The faster-acting phentolamine appears to be less effective and to have a shorter duration of action than sildenafil. Oral sildenafil is effective in about 70% of men who take it, whereas an adequate response with phentolamine is observed in only 35-40% of patients. Both compounds require erotic stimulation for efficacy. Since sildenafil indirectly increases blood flow in the systemic circulation by enhancing the smooth muscle relaxation effects of nitric oxide, it is contraindicated for patients with unstable heart conditions or cardiovascular disease, in particular patients taking nitrates, such as nitroglycerin, to treat angina. Other adverse effects associated with the clinical use of sildenafil include headache, flushing, dyspepsia, and xe2x80x9cabnormal vision,xe2x80x9d the latter the result of inhibition of the type VI phosphodiesterase isozyme (PDE-VI), a cyclic-GMP-specific phosphodiesterase that is concentrated in the retina. xe2x80x9cAbnormal visionxe2x80x9d is defined as a mild and transient xe2x80x9cbluishxe2x80x9d tinge to vision, but also an increased sensitivity to light or blurred vision.
Synthetic melanocortin receptor agonists (melanotropic peptides) have been found to initiate erections in men with psychogenic erectile dysfunction [See H. Wessells et al., xe2x80x9cSynthetic Melanotropic Peptide Initiates Erections in Men With Psychogenic Erectile Dysfunction: Double-Blind, Placebo Controlled Crossover Study,xe2x80x9d J. Urol., 160: 389-393 (1998); Fifteenth American Peptide Symposium, Jun. 14-19, 1997 (Nashville Tenn.)]. Activation of melanocortin receptors of the brain appears to cause normal stimulation of sexual arousal. In the above study, the centrally acting xcex1-melanocyte-stimulating hormone analog, melanotan-II (MT-II), exhibited a 75% response rate, similar to results obtained with apomorphine, when injected intramuscularly or subcutaneously to males with psychogenic erectile dysfunction. MT-II is a synthetic cyclic heptapeptide, Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2, which contains the 4-10 melanocortin receptor binding region common to xcex1-MSH and adrenocorticotropin, but with a lactam bridge. It is a non-selective MC-1R, -3R, -4R, and -5R agonist (Dorr et al., Life Sciences, Vol. 58, 1777-1784, 1996). MT-II (also referred to as PT-14) (Erectide(copyright)) is presently in clinical development by Palatin Technologies, Inc. and TheraTech, Inc. as a non-penile subcutaneous injection formulation. It is considered to be an xe2x80x9cinitiatorxe2x80x9d of the sexual response. The time to onset of erection with this drug is relatively short (10-20 minutes) with a duration of action approximately 2.5 hours. Adverse reactions observed with MT-II include nausea, flushing, loss of appetite, stretching, and yawning and may be the result of activation of MC-1R, MC-2R, MC-3R, and/or MC-5R. MT-II must be administered parenterally, such as by subcutaneous, intravenous, or intramuscular route, since it is not absorbed into the systemic circulation when given by the oral route. Compositions of melanotropic peptides and methods for the treatment of psychogenic erectile dysfunction are disclosed in U.S. Pat. No. 5,576,290, assigned to Competitive Technologies.
Because of the unresolved deficiencies of the various pharmacological agents discussed above, there is a continuing need in the medical arts for improved methods and compositions to treat individuals suffering from psychogenic and/or organic erectile dysfunction. Such methods and compositions should have wider applicability, enhanced convenience and ease of compliance, short onset of action, reasonably long duration of action, and minimal side effects with few contraindications, as compared to agents now available.
WO 99/64002 (published Dec. 16, 1999) discloses spiropiperidine derivatives as melanocortin receptor agonists which are useful for the treatment of obesity, diabetes mellitus, and sexual dysfunction.
It is therefore an object of the present invention to provide novel spiropiperidine derivatives which are useful as melanocortin receptor agonists.
It is another object of the present invention to provide novel spiropiperidine derivatives which are selective agonists of the melanocortin-4 (MC-4R) receptor.
It is another object of the present invention to provide pharmaceutical compositions comprising melanocortin receptor agonists.
It is another object of the present invention to provide methods for the treatment or prevention of disorders, diseases, or conditions responsive to the activation of the melanocortin receptor in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention.
It is another object of the present invention to provide compounds and pharmaceutical compositions useful for the treatment or prevention of obesity, diabetes mellitus, and male and/or female sexual dysfunction.
It is another object of the present invention to provide compounds and pharmaceutical compositions for the treatment or prevention of erectile dysfunction.
It is another object of the present invention to provide methods for the treatment or prevention of obesity, diabetes mellitus, and male and/or female sexual dysfunction.
These and other objects will become readily apparent from the detailed description that follows.
The present invention relates to novel spiropiperidine derivatives of structural formula (I): 
These spiropiperidine derivatives are effective as melanocortin receptor agonists and are particularly effective as selective melanocortin-4 receptor (MC-4R) agonists. They are therefore useful for the treatment and/or prevention of disorders responsive to the activation of MC-4R, such as obesity, diabetes as well as male and/or female sexual dysfunction, in particular, male erectile dysfunction.
The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutically acceptable carrier.
The present invention also relates to methods for the treatment or prevention of disorders, diseases, or conditions responsive to the activation of the melanocortin receptor in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention.
The present invention also relates to methods for the treatment or prevention of obesity, diabetes mellitus, and male and/or female sexual dysfunction by administering the compounds and pharmaceutical compositions of the present invention.
The present invention also relates to methods for treating erectile dysfunction by administering the compounds and pharmaceutical compositions of the present invention.
The present invention provides novel spiropiperidine derivatives of structural formula (I) or pharmaceutically acceptable salts thereof which are useful as melanocortin receptor agonists: 
wherein
Z is O, S, or NR4b;
n is 0, 1, or 2;
r is 1, 2, or3;
X is CHCO2R3, CHC(O)N(R3)2, NSO2R8, CHN(R3)COR8, CHN(R3)SO2R8, CHCH2OR3, or CHCH2heteroaryl;
Y is (CH2)r, CHC1-8 alkyl, O, Cxe2x95x90O, or SO2, with the proviso that when Y is O, the ring atom X is carbon;
Cy is benzene, pyridine, or cyclohexane;
R1 is selected from the group consisting of
hydrogen,
C1-8 alkyl,
(CHR7)nxe2x80x94C3-6 cycloalkyl,
(CHR7)nxe2x80x94O(CHR7)aryl,
(CHR7)naryl, and
(CHR7)nheteroaryl;
in which aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R6; and alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R6 and oxo;
R2 is selected from the group consisting of
hydrogen,
C1-8 alkyl,
(CH2)nC3-6 cycloalkyl, and
(CH2)n-aryl;
R3 is selected from the group consisting of
hydrogen,
C1-8 alkyl,
(CH2)n-aryl,
(CH2)nC3-6 cycloalkyl,
(CH2)n-heteroaryl, and
(CH2)n-heterocyclyl;
in which aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R6; and alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R6 and oxo;
or R3 and R5a and the carbons to which they are attached form a 5- to 7-membered ring optionally containing an additional heteroatom selected from O, S, and NR7;
or R3 and R4b and the carbons to which they are attached form a 5- to 7-membered ring optionally containing an additional heteroatom selected from O, S, and NR7;
R4a and R4b are each independently selected from the group consisting of
hydrogen,
amidino,
C1-8 alkyl,
(CH2)n-aryl,
(CH2)nC3-6 cycloalkyl,
(CH2)n-heteroaryl,
(CH2)n-heterocyclyl,
CO(CH2)0-1C(R7)2NH2,
COC(R7)2NHCO2R7,
COR7,
(CH2)nOR7,
(CH2)nCO2R7,
CH2Cxe2x89xa1CH,
CH2CHF2,
CONR7R7,
SO2R7, and
SO2NR7R7;
in which aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R6; and alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R6 and oxo;
or R4a and R2 and the carbons to which they are attached form a 5- to 7-membered ring optionally containing an additional heteroatom selected from O, S. and NR7; or
R4a and R4b and the atoms to which they are attached form a 5- to 7-membered ring;
R5a and R5b are each independently selected from the group consisting of
hydrogen,
C1-8 alkyl, and
C3-8 cycloalkyl;
wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R6 and oxo;
or R5a and R5b together with the carbons to which they are attached form a 5- to 7-membered ring;
R6 is selected from the group consisting of
hydrogen
C1-8 alkyl,
(CH2)n-aryl,
(CH2)nC3-7 cycloalkyl,
(CH2)n-heteroaryl,
halo,
OR7,
NHSO2R7,
N(R7)2,
Cxe2x89xa1N,
CO2R7,
C(R7)(R7)N(R7)2,
NO2,
SO2N(R7)2,
S(O)0-2R7,
CF3, and
OCF3;
each R7 is independently selected from the group consisting of
hydrogen,
C1-8 alkyl,
(CH2)n-aryl, and
(CH2)nC3-7 cycloalkyl;
each R8 is independently selected from the group consisting of
hydrogen,
C1-8 alkyl,
(CH2)n-aryl,
(CH2)n-heteroaryl,
(CH2)n-heterocyclyl,
(CH2)nC3-7 cycloalkyl,
(CH2)nN(R3)2,
(CH2)nNH-heteroaryl, and
(CH2)nNH-heterocyclyl;
wherein aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R6; and alkyl, cycloalkyl, heterocyclyl, and (CH2)n are unsubstituted or substituted with one to three groups independently selected from R6 and oxo;
or two R8 groups together with the atoms to which they are attached form a 5- to 8-membered mono- or bi-cyclic ring system optionally containing an additional heteroatom selected from O, S, NR7, NBoc, and NCbz; and
R9 is selected from the group consisting of
hydrogen,
halo,
C1-8 alkyl,
C1-6 alkoxy,
CN,
CF3, and
OCF3.
In one embodiment of the compounds of the present invention, Cy is benzene or cyclohexane. In a class of this embodiment, Cy is benzene.
In a second embodiment of the compounds of the present invention, R1 is CHR7-aryl, CHR7OCHR7-aryl, or CH(R7)-heteroaryl wherein aryl and heteroaryl are optionally substituted with one or two R6 groups. In a class of this embodiment, R1 is benzyl optionally substituted with one or two groups selected from halogen, C1-4 alkyl, C1-4 alkoxy, CF3, and OCF3. In a subclass of this class, R1 is 4-chlorobenzyl, 4-fluorobenzyl, or 4-methoxybenzyl.
In a third embodiment of the compounds of the present invention, Z is NR4b.
In a fourth embodiment of the compounds of the present invention, R4a and R4b are each independently selected from the group consisting of hydrogen,
amidino,
C1-8 alkyl,
(CH2)n-aryl,
(CH2)n-heteroaryl,
(CH2)n-heterocyclyl,
(CH2)nC3-6 cycloalkyl,
(CH2)nCO2R7,
CONR7R7,
COR7,
CO(CH2)0-1C(R7)2NH2,
COC(R7)2NHCO2R7,
(CH2)nOR7,
CH2Cxe2x89xa1CH,
CH2CHF2,
SO2R7, and
SO2NR7R7;
in which aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R6; and alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R6 and oxo;
or R4a and R4b and the atoms to which they are attached form a 6-membered ring;
R3, R5a, and R5b are each independently hydrogen, C1-4 alkyl, or aryl, wherein aryl is unsubstituted or substituted with one to three groups independently selected from R6; or R3 and R5a and the carbons to which they are attached form a 6-membered ring optionally containing an additional heteroatom selected from O, S, and NR7; or
R3 and R4b and the carbons to which they are attached form a 6-membered ring optionally containing an additional heteroatom selected from O, S, and NR7.
In a class of this embodiment, R4a and R4b are each independently selected from the group consisting of
hydrogen,
amidino,
C1-4 alkyl,
(CH2)0-1 aryl
(CH2)0-1-heteroaryl,
(CH2)0-1-heterocyclyl,
(CH2)0-1C3-6 cycloalkyl,
(CH2)0-1CO2R7,
CO(CH2)0-1C(Me)2NH2,
COC(Me)2NHCO2R7,
(CH2)2OR7,
COR7,
CONR7R7,
SO2R7, and
SO2NR7R7;
in which aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R6; and alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R6 and oxo;
R3, R5a, and R5b are each independently hydrogen, C1-4 alkyl, or phenyl, wherein phenyl is unsubstituted or substituted with one to three groups independently selected from R6; or R3 and R5a and the carbons to which they are attached form a 6-membered ring optionally containing an additional heteroatom selected from O, S, and NR7; or R3 and R4b and the carbons to which they are attached form a 6-membered ring optionally containing an additional heteroatom selected from O, S, and NR7.
In a fifth embodiment of the compounds of the present invention, R2 is H or CH3.
In a further embodiment of the present invention, there are provided compounds of structural formula Ia: 
wherein
X is CHCO2R3, CHC(O)N(R3)2, NSO2R8, CHN(R3)COR8, or CHN(R3)SO2R8;
R6 is hydrogen, halo, or methoxy;
R2 is hydrogen or methyl;
R9 is hydrogen or halo; and
R4a and R4b are each independently selected from the group consisting of
hydrogen,
amidino,
C1-4 alkyl,
(CH2)0-1 aryl
(CH2)0-1-heteroaryl,
(CH2)0-1-heterocyclyl,
(CH2)0-1C3-6 cycloalkyl,
CO2R7,
CO(CH2)0-1C(Me)2NH2,
COC(Me)2NHCO2R7,
(CH2)2OR7,
COR7,
CONR7R7,
SO2R7, and
SO2NR7R7;
in which aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R6; and alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R6 and oxo.
In a further embodiment of the present invention, there are provided compounds of structural formula Ia: 
wherein
R6 is hydrogen, halo, or methoxy;
R2 is hydrogen or methyl;
R9 is hydrogen or halo; and
R4a and R4b are each independently selected from the group consisting of
hydrogen,
C1-4 alkyl,
(CH2)0-1-aryl
(CH2)0-1-heteroaryl,
(CH2)0-1-heterocyclyl,
(CH2)0-1C3-6 cycloalkyl,
in which aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R6; and alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R6 and oxo.
In yet a further embodiment of compounds of formulae I, Ia, or Ib the carbon atom marked with * has the R configuration.
Illustrative but nonlimiting examples of the present invention are compounds of structural formula Ic shown below that are useful as melanocortin receptor agonists:
or a pharaceutically acceptable salt thereof.
The compounds of structural Formula I are effective as melanocortin receptor agonists and are particularly effective as selective agonists of the MC-4R. They are therefore useful for the treatment and/or prevention of disorders responsive to the activation of MC-4R, such as obesity, diabetes as well as male and/or female sexual dysfunction, in particular, erectile dysfunction, and further in particular, male erectile dysfunction.
Another aspect of the present invention provides a method for the treatment or prevention of obesity or diabetes in a mammal which comprises administering to said mammal an effective amount of a compound of formula I.
Another aspect of the present invention provides a method for the treatment or prevention of male or female sexual dysfunction including erectile dysfunction which comprises administering to a patient in need of such treatment or prevention an effective amount of a compound of formula I.
Yet another aspect of the present invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier.
Throughout the instant application, the following terms have the indicated meanings:
The alkyl groups specified above are intended to include those alkyl groups of the designated length in either a straight or branched configuration. Exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
The term xe2x80x9chalogenxe2x80x9d is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.
The term xe2x80x9carylxe2x80x9d includes phenyl and naphthyl.
The term xe2x80x9cheteroarylxe2x80x9d includes mono- and bicyclic aromatic rings containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. xe2x80x9c5- or 6-membered heteroarylxe2x80x9d are monocyclic heteroaromatic rings, examples thereof include thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, pyrazole, triazole, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like. Bicyclic heteroaromatic rings include, but are not limited to, benzothiadiazole, indole, benzothiophene, benzofuran, benzimidazole, benzisoxazole, benzothiazole, quinoline, benzotriazole, benzoxazole, isoquinoline, purine, furopyridine and thienopyridine.
The term xe2x80x9c5- or 6-membered carbocyclylxe2x80x9d is intended to include non-aromatic rings containing only carbon atoms such as cyclopentyl and cyclohexyl.
The term xe2x80x9c5 and 6-membered heterocyclylxe2x80x9d is intended to include non-aromatic heterocycles containing one to four heteroatoms selected from nitrogen, oxygen and sulfur. Examples of a 5 or 6-membered heterocyclyl include piperidine, morpholine, thiamorpholine, pyrrolidine, imidazolidine, tetrahydrofuran, piperazine, and the like.
Certain of the above defined terms may occur more than once in the above formula and upon such occurrence each term shall be defined independently of the other; thus for example, NR7R7 may represent NH2, NHCH3, N(CH3)CH2CH3, and the like.
The term xe2x80x9ccompositionxe2x80x9d, as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
xe2x80x9cErectile dysfunctionxe2x80x9d is a disorder involving the failure of a male mammal to achieve erection, ejaculation, or both. Symptoms of erectile dysfunction include an inability to achieve or maintain an erection, ejaculatory failure, premature ejaculation, or inability to achieve an orgasm. An increase in erectile dysfunction is often associated with age and is generally caused by a physical disease or as a side-effect of drug treatment.
By a melanocortin receptor xe2x80x9cagonistxe2x80x9d is meant an endogenous or drug substance or compound that can interact with a melanocortin receptor and initiate a pharmacological response characteristic of the melanocortin receptor. By a melanocortin receptor xe2x80x9cantagonistxe2x80x9d is meant a drug or a compound that opposes the melanocortin receptor-associated responses normally induced by another bioactive agent. The xe2x80x9cagonisticxe2x80x9d properties of the compounds of the present invention were measured in the functional assay described below. The functional assay discriminates a melanocortin receptor agonist from a melanocortin receptor antagonist.
By xe2x80x9cbinding affinityxe2x80x9d is meant the ability of a compound/drug to bind to its biological target, in the the present instance, the ability of a compound of formula I to bind to a melanocortin receptor. Binding affinities for the compounds of the present invention were measured in the binding assay described below and are expressed as IC50""s. xe2x80x9cEfficacyxe2x80x9d describes the relative intensity with which agonists vary in the response they produce even when they occupy the same number of receptors and with the same affinity. Efficacy is the property that enables drugs to produce responses. Properties of compounds/drugs can be categorized into two groups, those which cause them to associate with the receptors (binding affinity) and those that produce a stimulus (efficacy). The term xe2x80x9cefficacyxe2x80x9d is used to characterize the level of maximal responses induced by agonists. Not all agonists of a receptor are capable of inducing identical levels of maximal responses. Maximal response depends on the efficiency of receptor coupling, that is, from the cascade of events, which, from the binding of the drug to the receptor, leads to the desired biological effect.
The functional activities expressed as EC50""s and the xe2x80x9cagonist efficacyxe2x80x9d for the compounds of the present invention at a particular concentration were measured in the functional assay described below.
Compounds of Formula I contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of Formula I.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
Some of the compounds described herein may exist as tautomers such as keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of Formula I.
Compounds of the Formula I may be separated into their individual diastereoisomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof, or via chiral chromatography using an optically active stationary phase.
Alternatively, any diastereomer of a compound of the general Formula I or Ia may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, lithium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,Nxe2x80x2-dibenzylethylenediarine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, malonic, mucic, nitric, pamoic, pantothenic, phosphoric, propionic, succinic, sulfuric, tartaric, p-toluenesulfonic acid, trifluoroacetic acid, and the like. Particularly preferred are citric, fumaric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
Compounds of formula I are melanocortin receptor agonists and as such are useful in the treatment, control or prevention of diseases, disorders or conditions responsive to the activation of one or more of the melanocortin receptors including, but are not limited to, MC-1, MC-2, MC-3, MC-4, or MC-5. Such diseases, disorders or conditions include, but are not limited to, obesity (by reducing appetite, increasing metabolic rate, reducing fat intake or reducing carbohydrate craving), diabetes mellitus (by enhancing glucose tolerance, decreasing insulin resistance), hypertension, hyperlipidemia, osteoarthritis, cancer, gall bladder disease, sleep apnea, depression, anxiety, compulsion, neuroses, insomnia/sleep disorder, substance abuse, pain, male and female sexual dysfunction (including impotence, loss of libido and erectile dysfunction), fever, inflammation, immunemodulation, rheumatoid arthritis, skin tanning, acne and other skin disorders, neuroprotective and cognitive and memory enhancement including the treatment of Alzheimer""s disease. Some compounds encompassed by formula I show highly selective affinity for the melanocortin-4 receptor relative to MC-1R, MC-2R, MC-3R, and MC-5R, which makes them especially useful in the prevention and treatment of obesity, as well as male and/or female sexual dysfunction, including erectile dysfunction.
xe2x80x9cMale sexual dysfunctionxe2x80x9d includes impotence, loss of libido, and erectile dysfunction.
xe2x80x9cErectile dysfunctionxe2x80x9d is a disorder involving the failure of a male mammal to achieve erection, ejaculation, or both. Symptoms of erectile dysfunction include an inability to achieve or maintain an erection, ejaculatory failure, premature ejaculation, or inability to achieve an orgasm. An increase in erectile dysfunction and sexual dysfunction can have numerous underlying causes, including but not limited to (1) aging, (b) an underlying physical dysfunction, such as trauma, surgery, and peripheral vascular disease, and (3) side-effects resulting from drug treatment, depression, and other CNS disorders.
xe2x80x9cFemale sexual dysfunctionxe2x80x9d can be seen as resulting from multiple components including dysfunction in desire, sexual arousal, sexual receptivity, and orgasm related to disturbances in the clitoris, vagina, periurethral glans, and other trigger points of sexual function. In particular, anatomic and functional modification of such trigger points may diminish the orgasmic potential in breast cancer and gynecologic cancer patients. Treatment of female sexual dysfunction with an MC-4 receptor agonist can result in improved blood flow, improved lubrication, improved sensation, facilitation of reaching orgasm, reduction in the refractory period between orgasms, and improvements in arousal and desire. In a broader sense, xe2x80x9cfemale sexual dysfunctionxe2x80x9d also incorporates sexual pain, premature labor, and dysmenorrhea.
Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of Formula I are administered orally or topically.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
When treating obesity, in conjunction with diabetes and/or hyperglycemia, or alone, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.001 milligram to about 100 milligrams per kilogram of animal body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form. In the case of a 70 kg adult human, the total daily dose will generally be from about 0.07 milligrams to about 3500 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
When treating diabetes mellitus and/or hyperglycemia, as well as other diseases or disorders for which compounds of formula I are useful, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.001 milligram to about 100 milligram per kilogram of animal body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form. In the case of a 70 kg adult human, the total daily dose will generally be from about 0.07 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
For the treatment of sexual dysfunction compounds of the present invention are given in a dose range of 0.001 milligram to about 100 milligram per kilogram of body weight, preferably as a single dose orally or as a nasal spray.
Compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula I are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of Formula I is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula I. Examples of other active ingredients that may be combined with a compound of Formula I, either administered separately or in the same pharmaceutical compositions, include, but are not limited to:
(a) insulin sensitizers including (i) PPARxcex3 agonists such as the glitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555, BRL49653 and the like), and compounds disclosed in WO97/27857, 97/28115, 97/28137 and 97/27847; (ii) biguanides such as metformin and phenformin;
(b) insulin or insulin mimetics;
(c) sulfonylureas, such as tolbutamide and glipizide;
(d) xcex1-glucosidase inhibitors (such as acarbose),
(e) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and other statins), (ii) sequestrants (cholestyramine, colestipol and a dialkylaminoalkyl derivatives of a cross-linked dextran), (ii) nicotinyl alcohol nicotinic acid or a salt thereof, (iii) proliferator-activater receptor xcex1 agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate), (iv) inhibitors of cholesterol absorption for example beta-sitosterol and (acyl CoA:cholesterol acyltransferase) inhibitors for example melinamide, (v) probucol, (vi) vitamin E, and (vii) thyromimetics;
(f) PPARxcex4 agonists, such as those disclosed in WO97/28149;
(g) antiobesity compounds, such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, or xcex23 adrenergic receptor agonists;
(h) feeding behavior modifying agents, such as neuropeptide Y antagonists (e.g. neuropeptide Y5) such as those disclosed in WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822 and WO 97/20823;
(i) PPARxcex1 agonists such as described in WO 97/36579 by Glaxo;
(j) PPARxcex3 antagonists as described in WO97/10813;
(k) serotonin reuptake inhibitors such as fluoxetine and sertraline;
(l) growth hormone secretagogues such as MK-0677; and
(m) agents useful in the treatment of male and/or female sexual dysfunction, such as type V cyclic-GMP-specific phosphodiesterase (PDE-V) inhibitors, including sildenafil and IC-351; alpha-adrenergic receptor antagonists, including phentolamine and yohimbine and pharmaceutically acceptable salts thereof; and dopamine receptor agonists, such as apomorphine.
In one embodiment of a combination for the treatment of male or female sexual dysfunction, the second ingredient to be combined with a compound of Formula I can be a type V cyclic-GMP-specific phosphodiesterase (PDE-V) inhibitor, such as sildenafil and IC-351 or a pharmaceutically acceptable salt thereof; an alpha-adrenergic receptor antagonist, such as phentolamine and yohimbine or a pharmaceutically acceptable salt thereof; or a dopamine receptor agonist, such as apomorphine or a pharmaceutically acceptable salt thereof.
Another aspect of the present invention provides pharmaceutical compositions which comprises a compound of Formula I and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
In practical use, the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray.
The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
Compounds of formula I may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
In the Schemes and Examples below, various reagent symbols and abbreviations have the following meanings:
The novel compounds of the present invention can be prepared according to the procedure of the following schemes and examples, using appropriate materials and are further exemplified by the following specific examples. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted.
The following Schemes and Examples describe procedures for making representative compounds of the present invention. Moreover, by utilizing the procedures and intermediates described in detail in PCT International Application Publication No. WO 99/64002 (Dec. 16, 1999), PCT International Application Publication No. WO 00/74679 (Dec. 14, 2000), and U.S. Pat. No. 5,536,716, the contents of all of which are incorporated by reference herein in their entirety, in conjunction with the disclosure contained herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein.
The phrase xe2x80x9cstandard peptide coupling reaction conditionsxe2x80x9d means coupling a carboxylic acid with an amine using an acid activating agent such as EDC, DCC, and BOP in a inert solvent such as dichloromethane in the presence of a catalyst such as HOBT. The use of protecting groups for amine and carboxylic acid to facilitate the desired reaction and minimize undesired reactions is well documented. Conditions required to remove protecting groups are found in standard textbooks such as Greene, T, and Wuts, P. G. M., Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., New York, N.Y., 1991. CBZ and BOC are commonly used protecting groups in organic synthesis, and their removal conditions are known to those skilled in the art. For example, CBZ may be removed by catalytic hydrogenation with hydrogen in the presence of a noble metal or its oxide such as palladium on activated carbon in a protic solvent such as ethanol. In cases where catalytic hydrogenation is contraindicated due to the presence of other potentially reactive functionality, removal of CBZ groups can also be achieved by treatment with a solution of hydrogen bromide in acetic acid, or by treatment with a mixture of TFA and dimethylsulfide. Removal of BOC protecting groups is carried out in a solvent such as methylene chloride or methanol or ethyl acetate, with a strong acid, such as trifluoroacetic acid or hydrochloric acid or hydrogen chloride gas.
It is understood that in some cases the order of carrying out the reaction schemes below may be varied to facilitate the reaction or to avoid unwanted reaction products. 